Necrosis and apoptosis are two distinct modes of death for nucleated eukaryotic cells. Necrosis may occur as a result of cellular injury, typically complement attack, lytic viral infection, toxins and the like. Apoptosis or "programmed cell death", on the other hand, is the physiological process of cell death that functions to control cell populations during embryogenesis, immune responses, hormone withdrawal from dependent tissues, normal tissue homeostasis, and regressing tumors, as described in Duvall, E., et al. (1986) Immunol. Today 7, 115-119; Walker, N. I., et al. (1988) Meth. Achiev. Exp. Pathol. 13, 18-54; and Gerschenson, L. E. et al. (1992) FASEB J. 6, 2450-2455. Unlike cellular necrosis, apoptotic cytolysis is not usually associated with cellular injury. Apoptosis may be induced by immunologically mediated methods, such as antibody dependent cell cytotoxicity (K cell attack), viral infection, and attack by cytotoxic T lymphocyte effector cells, lymphotoxins, or natural killer (NK) cells. Further, apoptosis may be induced in tumor cells by a variety of physical, chemical, and biochemical apoptosis inducing agents, including gamma radiation, UV light, heat shock, cold shock, cisplatin, etoposide, teniposides, DNA alkylating agents, macromolecular synthesis inhibitors, and the like.
Cytological and biochemical changes are associated with the cellular apoptotic process. The cytoplasm condenses, and the endoplasmic reticulum dilates to form vesicles which fuse with the cell membrane, producing characteristic cellular morphology. Changes in the nuclei include the formation of dense crescent shaped aggregates of chromatin, nucleolus fragmentation, and formation of vesicles at or on the nuclear membrane. During apoptosis endonucleases present in the cell cut the DNA in the linker regions between nucleosomes to release DNA fragments in integer multiples of 180-190 base pairs, Cohen J. J., et al. (1984) J. Immunol. 132, 38-42. The pattern of cleavage is believed to result from the vulnerability of the linker DNA between the nucleosomes to endonucleases.
However, the identification of the relevant nucleases involved in apoptosis has not yet been achieved. Similarly, the elucidation of the cellular signalling transduction mechanisms beginning with the apoptosis inducing agent and leading to endonuclease activation have not been determined.
Therefore, it would be useful to provide compositions and methods for modulating cell growth and proliferation by regulation of the apoptotic signalling pathway. The compositions would have particular therapeutic utility where cell growth or proliferation is aberrant, for example, as anti-neoplastic agents. The present invention solves these and other related needs.